Therapy for vitiligo

ABSTRACT

The present invention relates to a therapy for vitiligo. In particular the present invention provides a pharmaceutical composition comprising an alpha melanocyte stimulating hormone (alpha-MSH) analogue either alone, in combination with narrow band UVB and/or in combination with one or more corticosteroids, immunosuppressants, anti-inflammatory agents and/or photochemotherapeutic agents for the treatment or prevention of vitiligo.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This is a continuation of U.S. patent application Ser. No. 13/801,816,filed on Mar. 13, 2013, which is a continuation-in-part of U.S. patentapplication Ser. No. 12/934,024, filed on Feb. 8, 2011, which is a U.S.national stage entry of International Patent Application No.PCT/EP2009/002265, filed on Mar. 27, 2009, which claims priority toAustralian Patent Application No. 2008901461, filed on Mar. 27, 2008,the entire contents of all of which are fully incorporated herein byreference.

INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY

Incorporated by reference in its entirety herein is a computer-readablenucleotide/amino acid sequence listing submitted concurrently herewithand identified as follows: One 31,048 Byte ASCII (Text) file named“5120PAF-030267-1010-US02-SEQ-LIST-09-25-17.txt” created on Sep. 25,2017.

FIELD OF THE INVENTION

The present invention relates to a therapy for vitiligo. In particularthe present invention provides a pharmaceutical composition comprisingan alpha melanocyte stimulating hormone (alpha-MSH) analogue eitheralone or in combination with one or more corticosteroid,immunosuppressant, anti-inflammatory agent and/or photochemotherapeuticagent for the treatment or prevention of vitiligo.

BACKGROUND OF THE INVENTION

Vitiligo is a chronic skin condition that causes loss of pigment,including melanin, resulting in irregular pale patches of skin. Theprecise etiology of vitiligo is complex and not fully understoodalthough there is some evidence to suggest it is caused by a combinationof auto-immune, genetic and environmental factors.

As many as 50% of people with vitiligo develop patches of de-pigmentedskin appearing on extremities before their 20 s. The patches may grow orremain constant in size and often occur symmetrically across both sideson the body. Occasionally small areas may repigment as they are“recolonised” by melanocytes and following melanin production andrelease. The location of vitiligo affected skin changes overtime, withsome patches re-pigmenting and others becoming affected. In some cases,mild trauma to an area of skin seems to cause new patches, for example,around the ankles (caused by friction with shoes or sneakers). Vitiligomay also be caused by stress factors that affect the immune system,causing the body to react or respond by “eliminating” or gradually loosethe ability to produce and release melanin, skin pigment. Further,Vitiligo on the scalp may also affect the colour of the hair leavingwhite patches or streaks, with similar effects observed for facial andbody hair.

There are a number of ways to alter the appearance of vitiligo withoutaddressing its underlying cause. In mild cases, vitiligo patches can behidden with makeup or other cosmetic solutions. If the affected personis pale-skinned, the patches can be made less visible by avoidingsunlight and the sun tanning of unaffected skin. However, exposure tosunlight may also cause the melanocytes to regenerate to allow thepigmentation to come back to its original colour.

Treatment options include medical treatments, surgical therapies,phototherapy and adjunctive treatments. Pharmaceuticals include topicalsteroid therapy, topical or oral psoralen phototherapy anddepigmentation. Surgical therapies include skin grafts, melanocytetransplantations and micropigmentation or tattooing, while adjunctivetherapies include sunscreens and cosmetics.

Despite the fact that many treatment options are available, each suffersfrom its own disadvantages and inherent limitations. For example,phototherapy involves exposing an individual to narrow band UV-B light(NB-UVB) resulting in skin repigmentation. Although phototherapyprovides an effective short-term treatment option, repetitive exposureto NB-UVB light is needed to achieve continuous repigmentation. Further,while the frequency of exposure to NB-UVB light varies from individualto individual, repetitive exposure may result in unwanted side-effectsincluding mild burning, blistering and skin irritations. Foremost, therepetitive treatment by UVB increases the risk of inducing skinmalignancies, e.g. squamous cell carcinomas and basal cell carcinomas[Journal of Investigative Dermatology (2005) 124, 505-513; High Levelsof Ultraviolet B Exposure Increase the Risk of Non-Melanoma Skin Cancerin Psoralen and Ultraviolet A—Treated Patients] [Mayo Clinics update].

Topical corticosteroid therapy has a reported success rate of up to 56%,however, long-term use of corticosteroids can result in thinning of theskin, stretch marks, and dilation of blood vessels. Further, treatmentwith oral or topical psoralen plus UVA (PUVA) has proven successful,however, patients need to ingest or apply psoralen before receiving thelight treatment, and long term use of oral PUVA for the treatment ofpsoriasis has been associated with an increased incidence of skincancer.

While immunomodulator creams are believed to cause repigmentation thereis little or no scientific support to back this claim.

A need therefore exists to develop more effective treatments forvitiligo.

SUMMARY OF THE INVENTION

In a first aspect of the present invention there is provided a methodfor treating or preventing vitiligo in a subject comprisingadministering to the subject a therapeutically or prophylacticallyeffective amount of an alpha-MSH analogue.

In a second aspect of the present invention there is provided the use ofan alpha-MSH analogue for the manufacture of a prophylactic ortherapeutic agent for the treatment or prevention of vitiligo in asubject.

In a preferred embodiment the method further comprises administering tothe subject one or more agents selected from the group consisting ofcorticosteroids, immunosuppressants, anti-inflammatory agents and aphotochemotherapeutic agents.

In a third aspect of the present invention there is provided apharmaceutical composition for treating or preventing vitiligocomprising an alpha-MSH analogue and one or more agents selected fromthe group consisting of corticosteroids, immunosuppressants,anti-inflammatory agents and a photochemotherapeutic agents togetherwith a pharmaceutically acceptable carrier or diluent.

In a fourth aspect of the present invention there is provided a methodfor treating or preventing vitiligo in a subject comprisingadministering to the subject a therapeutically or prophylacticallyeffective amount of a pharmaceutical composition according to the thirdaspect of the invention.

In a fifth aspect of the present invention there is provided the use ofan effective amount of a pharmaceutical composition according to thethird aspect of the invention for the manufacture of a prophylactic ortherapeutic medicament for the treatment or prevention of vitiligo in asubject.

In a sixth aspect of the present invention, there is provided a methodfor treating or preventing vitiligo in a subject comprisingadministering to the subject a therapeutically or prophylacticallyeffective amount of an alpha-MSH analogue, further comprising the stepof exposing the subject to an effective amount of narrow bandultraviolet B (NB UVB) light.

DETAILED DESCRIPTION OF THE INVENTION

Before the present methods are disclosed and described, it is to beunderstood that the aspects described below are not limited to specificmethods or uses as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular aspects only and is not intended to be limiting.

In this specification and in the claims that follow, reference will bemade to a number of terms that shall be defined to have the followingmeanings: It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a pharmaceutical carrier” includes mixtures oftwo or more such carriers, and the like.

The terms “optional” or “optionally” as used herein means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where the event or circumstanceoccurs and instances where it does not.

Ranges may be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value.

Similarly, when values are expressed as approximations, by use of theantecedent “about” it will be understood that the particular value formsanother aspect. It will be further understood that the endpoints of eachof the ranges are significant both in relation to the other endpoint,and independently of the other endpoint.

References in the specification and concluding claims to parts byweight, of a particular element or component in a composition orarticle, denotes the weight relationship between the element orcomponent and any other elements or components in the composition orarticle for which a part by weight is expressed. Thus, in a compoundcontaining 2 parts by weight of component X and 5 parts by weightcomponent Y, X and Y are present at a weight ratio of 2:5, and arepresent in such ratio regardless of whether additional components arecontained in the compound.

A weight percent of a component, unless specifically stated to thecontrary, is based on the total weight of the formulation or compositionin which the component is included.

The term “contacting” as used herein is meant an instance of exposure byclose physical contact of at least one substance to another substance.For example, contacting can include contacting a substance, such as apharmacologic agent, with a cell. A cell can be contacted with a testcompound, for example, an analogue of alpha-MSH, by adding the agent tothe culture medium (by continuous infusion, by bolus delivery, or bychanging the medium to a medium that contains the agent) or by addingthe agent to the extracellular fluid in vivo (by local delivery,systemic delivery, intravenous injection, bolus delivery, or continuousinfusion). The duration of contact with a cell or group of cells isdetermined by the time the test compound is present at physiologicallyeffective levels or at presumed physiologically effective levels in themedium or extracellular fluid bathing the cell.

The terms “prophylactic treatment”, “prevention” or “preventing” as usedherein mean the administration of an active compound or composition to asubject at risk for an undesirable condition. The condition can includea disease, disorder or reaction, or a predisposition to a disease,disorder or reaction. Prophylactic treatment can range from a reductionin the risk for the condition or of the severity of the condition to thecomplete prevention of the condition.

The terms “therapeutic treatment” and “treating” mean the administrationof an active compound or composition to a subject having an undesirablecondition such as a disease, disorder or reaction. Therapeutic treatmentcan range from reduction in the severity of the condition in the subjectto the complete recovery of the subject from the condition.

The term “effective amount and time” as used herein means a therapeuticamount and time needed to achieve the desired result or results, e.g.,preventing or treating photosensitivity associated with UVR exposure ina subject.

The term “induce” as used herein means initiating a desired response orresult that was not present prior to the induction step. The term“induce” also includes the term “potentiate”.

The term “intermittent” as used herein means administering an activecompound or composition in a series of discreet doses over a determinedperiod, e.g., a period of sustained release comprising of greater than24 hours of an alpha-MSH analogue for up to 3 months.

The term “potentiate” as used herein means sustaining a desired responseat the same level prior to the potentiating step or increasing thedesired response over a period of time.

The term “melanogenesis” as used herein is defined as the ability of asubject to produce melanins by melanin-producing cells, or melanocytes.

The term “epidermal tissue” as used herein includes in particular theskin of a subject.

The invention pertains to methods and compositions for treatment ofvitiligo utilising an alpha-MSH analogue.

In a first aspect of the present invention there is provided a methodfor treating or preventing vitiligo in a subject comprisingadministering to the subject a therapeutically or prophylacticallyeffective amount of an alpha-MSH analogue.

In a second aspect of the present invention there is provided the use ofan alpha-MSH analogue for the manufacture of a prophylactic ortherapeutic agent for the treatment or prevention of vitiligo in asubject.

In a preferred embodiment the method further comprises administering tothe subject one or more agents selected from the group consisting ofcorticosteroids, immunosuppressants, anti-inflammatory agents and aphotochemotherapeutic agents.

In a third aspect of the present invention there is provided apharmaceutical composition for treating or preventing vitiligocomprising an alpha-MSH analogue and one or more agents selected fromthe group consisting of corticosteroids, immunosuppressants,anti-inflammatory agents and a photochemotherapeutic agents togetherwith a pharmaceutically acceptable carrier or diluent.

In a fourth aspect of the present invention there is provided a methodfor treating or preventing vitiligo in a subject comprisingadministering to the subject a therapeutically or prophylacticallyeffective amount of a pharmaceutical composition according to the thirdaspect of the invention.

In a fifth aspect of the present invention there is provided the use ofan effective amount of a pharmaceutical composition according to thethird aspect of the invention for the manufacture of a prophylactic ortherapeutic medicament for the treatment or prevention of vitiligo in asubject.

In a sixth aspect of the present invention, there is provided a methodfor treating or preventing vitiligo in a subject comprisingadministering to the subject a therapeutically or prophylacticallyeffective amount of an alpha-MSH analogue, further comprising the stepof exposing the subject to an effective amount of narrow bandultraviolet B (NB UVB) light.

Preferably the subject is a human or domestic animal subject. Mostpreferably the subject is a human subject.

It is also preferred that treatment with the alpha-MSH analoguecommences as early as possible following appearance of the condition.

Alpha-MSH is released from UVR exposed keratinocytes in human skinfollowing exposure to ultraviolet radiation. It is understood to act onthe melanocortin-1-receptors (MC1R) to, exclusively in melanocytes,induce synthesis of the brownish-black melanin pigment. MC1R areexpressed on keratinocytes as well as number of other cells including,but not exclusively, immunological cells such as dendritic/Langerhanscells, neutrophils, microglia and monocytes as well as astrocytes, andendothelial cells.

It has previously been disclosed that a super-potent derivative ofalpha-MSH, Nle⁴-D-Phe⁷-alpha-MSH, can induce melanin synthesis in humanvolunteers. Nle⁴-D-Phe⁷-alpha-MSH contains two amino acid substitutionsand is approximately 10 to 1,000-fold more potent than the nativehormone at inducing pigmentation in experimental systems such as thefrog skin bioassay or in cultured human keratinocytes.

The term “alpha-MSH analogue” as used herein is defined as a derivativeof alpha-MSH which exhibits agonist activity for the melanocortin-1receptor (MC1R), the receptor to which alpha-MSH binds to initiate theproduction of melanin within a melanocyte. Such derivatives includederivatives in which (i) one or more amino acid residues are deletedfrom the native alpha-MSH molecule at the N-terminal end, the C-terminalend, or both; and/or (ii) one or more amino acid residues of the nativealpha-MSH molecule are replaced by another natural, non-natural orsynthetic amino acid residue; and/or (iii) an intramolecular interactionforms as a cyclic derivative.

The use of any alpha-MSH analogue is contemplated in the methodsdescribed herein. Several derivatives of alpha-MSH have beensynthesized. In one aspect of the present invention, the alpha-MSHanalogues described in U.S. Pat. Nos. 4,457,864, 4,485,039, 4,866,038,4,918,055, 5,049,547, 5,674,839 and 5,714,576 and 4,918,055 and5,683,981, which are herein incorporated by reference for theirteachings with respect to alpha-MSH analogues and their synthesisthereof, can be used herein.

In one aspect of the present invention, the alpha-MSH analogue may be acompound as disclosed in Australian Patent No. 597630, selected fromcompounds of the formula:R₁—W—X—Y—Z—R₂

-   -   wherein    -   R₁ is absent, n-Pentadecanoyl, Ac, 4-phenylbutyrul, Ac-Gly-,        Ac-Met-Glu, Ac-Nle-    -   Glu-, or Ac-Tyr-Glu-;    -   W is -His- or -D-His-;    -   X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pNO₂)D-Phe⁷-;    -   Y is -Arg- or -D-Arg-;    -   Z is -Trp- or -D-Trp-; and    -   R₂ is —NH₂; -Gly-NH₂; or -Gly-Lys-NH₂.

In another aspect, the alpha-MSH analogue maybe selected from cyclicanalogues which are disclosed in Australian Patent No. 618733 where anintramolecular interaction (such as a disulfide or other covalent bond)exists (1) between the amino acid residue at position 4 and an aminoacid residue at position 10 or 11, and/or (2) between the amino acidresidue at position 5 and the amino acid residue at position 10 or 11.

The alpha-MSH analogue may be a linear analogue as disclosed in U.S.Pat. No. 5,674,839, selected from the group consisting of:

Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly- Pro-Val-NH₂,Ac-Ser-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly- Pro-Val-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Orn-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Orn-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dab-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dab-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dpr-NH₂,Ac-Nle-Glu-His-Phe-Arg-Trp-Lys-NH₂, andAc-Nle-Asp-His-Phe-Arg-Trp-Lys-NH₂.

The alpha-MSH analogue may also be a cyclic analogue as disclosed inU.S. Pat. No. 5,674,839, selected from the group consisting of:

wherein Ala=alanine, Arg=arginine, Dab=2,4-diaminobutyric acid,Dpr=2,3-diaminopropionic acid, Glu=glutamic acid, Gly=glycine,His=histidine, Lys=lysine, Met=methionine, Nle=norleucine,Orn=ornithine, Phe=phenylalanine, (pNO2)Phe=paranitrophenylalanine,Plg=phenylglycine, Pro=proline, Ser=serine, Trp=tryptophan,TrpFor=N¹⁻-formyl-tryptophan, Tyr=tyrosine, Val=valine.

All peptides are written with the acyl-terminal end at the left and theamino terminal end to the right; the prefix “D” before an amino aciddesignates the D-isomer configuration, and unless specificallydesignated otherwise, all amino acids are in the L-isomer configuration.

In one aspect of the present invention, the alpha-MSH analogue can be

In a further aspect, the alpha-MSH analogue is:

[Nle⁴, D-Phe⁷]-alpha-MSH₄₋₁₀, [Nle⁴, D-Phe⁷]-alpha-MSH₄₋₁₁,[Nle⁴, D-Phe⁷, D-Trp⁹]-alpha-MSH₄₋₁₁, or [Nle⁴, D-Phe⁷]-alpha-MSH₄₋₉.

In a particularly preferred aspect, the alpha-MSH analogue is [Nle⁴,D-Phe⁷]-alpha-MSH.

The pharmaceutical composition according to the first aspect of theinvention further comprises one or more agents selected from the groupconsisting of corticosteroids, immunosuppressants, anti-inflammatoryagents and photochemotherapeutic agents.

The corticosteroid according to the invention may be selected from thegroup consisting of mometasone furoate, betamethasone, dexamethasone,hydrocortisone, methylprednisolone. prednisolone and cortisone. It isparticularly preferred that the corticosteroid is mometasone furoate orbetamethasone.

The immunosuppressant according to the invention may be selected fromthe group consisting of cytostatics including cytotoxic antibiotics,alkylating agents and antimetabolites, antibodies, glucocorticoids,drugs acting on immunophilins including cyciosporine, tacrolimus andsirolimus, interferons, azathioprine, 5-fluorouracil and opioids. It isparticularly preferred that the immunosuppressant is selected from thegroup consisting of tacrolimus, betamethasone, azathioprine andlevamisole.

The anti-inflammatory agent according to the invention may be selectedfrom the group consisting of betamethasone, cortisone. It isparticularly preferred that the anti-inflammatory agent is betamethasoneor cortisone.

It is preferred that the photochemotherapeutic agent according to theinvention is psoralen.

As will be appreciated by a person skilled in the art, corticosteroidsaccording to the invention may act as an immunosuppressant and/oranti-inflammatory agent. For example, the dipropionate salt ofbetamethasone (trade name Diprosone) is a glucocorticoid which acts asboth an immunosuppressant and an anti-inflammatory agent.

In a second aspect of the present invention there is provided a methodfor treating or preventing vitiligo in a subject comprisingadministering to the subject a therapeutically or prophylacticallyeffective amount of a pharmaceutical composition according to the firstaspect of the invention.

In a preferred embodiment, the method according to the second aspect ofthe invention further comprises the step of exposing the subject to aneffective amount of ultra-violet A light (UVA) when the pharmaceuticalcomposition administered to the subject comprises one or morephotochemotherapeutic agents.

It is known to persons skilled in the art that photochemotherapeuticagents such as psoralens make the skin sensitive to ultra-violet (UV)light, particularly the long wavelength UVA light. Administration ofpsoralen prior to UVA exposure is known to be effective for treatingvitiligo.

Accordingly in a preferred aspect of the present invention thepharmaceutical composition is administered to the subject prior toexposure to UVA light.

In a sixth aspect of the present invention, there is provided a methodfor treating or preventing vitiligo in a subject comprisingadministering to the subject a therapeutically or prophylacticallyeffective amount of an alpha-MSH analogue, further comprising the stepof exposing the subject to an effective amount of UV light, preferablyUVB, more preferably narrow band ultraviolet B (NB UVB) light.

Preferably, the subject is treated with a combination of NB UVB lightand alpha-MSH analogue. Preferably the invention is directed to at leastpartially exposing the subject to the NB UVB light and simultaneously tothe alpha-MSH analogue. During exposure to the alpha MSH analogue, thesubject is preferably exposed to NB UVB light treatment. This results inexposure to the combination at the same time. In other words, thesubject is preferably at least partially treated with NB UVB light whilebeing exposed to the alpha MSH analogue, i.e. the subject is at leastpartially simultaneously exposed to both. Preferably, exposure of thesubject to NB UVB light at least partially overlaps with exposure to thealpha-MSH analogue.

The period of the combination treatment is at least 2 months, morepreferably at least 3 months, most preferably at least 4 months andpreferably at most 12 months, more preferably at most 7 months. Apreferred example is 3 months. Another preferred example is 4 months.Another preferred example is 6 months. Another preferred example is 7months.

Preferably, the subject is treated with NB UVB light before exposure tothe alpha MSH analogue and preferably for a period of at least 1 week,more preferably at least 2 weeks, most preferably at least one month andpreferably up to 12 months. This may be called a NB UVBpre-combination-treatment step.

Preferably, the subject is treated with NB UVB light after exposure tothe alpha MSH analogue and preferably for a period of at least 1 week,more preferably at least 2 weeks, most preferably at least one month, inparticular at least 5 weeks and even more particular at least 6 weeksand preferably up to 24 months. This may be called a NB UVBpost-combination-treatment step.

The present invention preferably uses UVB light treatment. UVB treatmentmay use Broad Band UVB (BB UVB using wavelengths of from 280 to 330 nm)but preferably uses narrow band UVB (NB UVB). Preferably, NB-UVB lighttreatment uses a wavelength of from 308 to 315 nm, preferably of from310 to 312 nm, more preferably 311 nm. Preferably, at least 40% of theirradiation (in terms of W/cm²) is within these ranges, more preferablyat least 60%, most preferably at least 80%. A further NB-UVB option isthe use of a 308 nm xenon-chloride excimer laser. Preferably, the UVirradiance of the spectrum below 300 nm is less than 50% (in W/cm²) ofthe total irradiance of the UVB light, more preferably less than 20%,most preferably less than 5% of the UVB light. This way most unwantedside-effects of repetitive UVB treatment may be avoided.

Preferably, irradiation is at least 150 mJ/cm² and preferably at most3000 mJ/cm². Preferably irradiation level of the next treatment is basedon the erythema occurring in the previous UVB treatment. Preferably, thedose is increased by up to 15% or decreased by up to 10%. Depending onany erythema formation of the previous treatment, the dose is preferablyincreased by 10-15% if no erythema occurred; the dose is kept the sameif minimal erythema occurred; or the dose is reduced by 5-10% if mild tomoderate erythema occurred. In this last instance, the treating doctormay decide not to give a dose given and in the next treatment either usethe last tolerated dose or the scheduled dose.

Preferably, NB UVB treatment takes less than 20 minutes, more preferablyless than 10 minutes. NB-UVB is preferably used for less than 6 minutes,for instance maximum 5 minutes.

Preferably, UVB (preferably NB-UVB) light treatment involves repetitiveexposure to UVB light. Preferably, the subject is treated with at least10 NB UVB treatments per month, more preferably twice or thrice weekly.Preferably UVB light treatment occurs on non-consecutive days.

Preferably, the subject is exposed to NB UVB treatment for a period ofat least 3 months, more preferably at least 4 most, most preferably atleast 5 months, in particularly preferred for a period of at least 6months and preferably up to 24 months, more preferably 18 months.

Preferred NB-UVB treatment regimen steps are as follows:

1. The subject is exposed for a period of 1 month with thrice weekly NBUVB light of 311 nm with an irradiation of from 150 to 3000 mJ/cm2 for aperiod of less than 5 minutes.

2. Subsequently, the subject is treated for a period of 4 months with acombination of:

-   -   thrice weekly NB UVB light treatments of 311 nm with an        irradiation of from 150 to 3000 mJ/cm2 for a period of 5        minutes;    -   monthly administered 16 mg afamelanotide implants, exposing the        subject to a level of 0.001 to 10 ng/ml afamelanotide in the        blood plasma for a period of from 5 to 10 days; and        3. Then, the subject is exposed for a period of 1 month with        thrice weekly NB UVB light of 311 nm with an irradiation of from        150 to 3000 mJ/cm2 for a period of 5 minutes.

In another preferred embodiment, the treatment regimen step 2 takes 3months. In further preferred embodiment, the treatment regimen step 2takes 5 months. In further preferred embodiment, the treatment regimenstep 2 takes 6 months. In another preferred embodiment, the treatmentregimen step 2 takes 7 months.

The alpha MSH analogue for treatment of vitiligo according to theinvention is preferably systemically administered by injection. Theinjection is preferably subcutaneous, intramuscular, intraperitoneal orintravenous. An implant is a preferred example of an injection. Furtherinformation on a preferred subcutaneous implant is provided inWO2006/012667 incorporated herein by reference.

A preferred effective amount of the alpha-MSH analogue is represented bythe following.

Preferably, the subject is exposed to the alpha MSH analogue at a levelof 0.001 ng/ml to 10 ng/ml in the plasma of the subject in the treatmentof vitiligo. Preferably, the subject is exposed to the alpha MSHanalogue after administration of the alpha-MSH analogue for a period ofat least 1 day, more preferably 2 days, most preferably a least 4 days,in particular at least 6 days. Other preferred periods are at least 8days, more preferably at least 10 days and most preferably at least 12days.

Preferably, the subject is treated with the alpha-MSH analogue withimplants at least weekly, more preferably at least monthly andpreferably for a period of at least 2 months, more preferably at least 3months, most preferably at least 4 months and preferably at most 12months, more preferably at most 7 months. A preferred example is 3months. Another preferred example is 4 months. Another preferred exampleis 6 months. Another preferred example is 7 months.

A preferred embodiment of the invention is a monthly implant comprisesfrom 10 to 25 mg of afamelantoide (preferably 16 mg) that is releasedover a period of between 7 and 10 days after implantation providingblood plasma levels between 0.001 and 10 ng/ml during this period.

Surprisingly, we have found that the invention is particularlybeneficial to subjects with Fitzpatrick skin types Ill to VI, morepreferably IV to VI, and most preferably V to VI. Generally, the darkerskin of subjects with higher Fitzpatrick skin types contrasts with palevitiliginous skin lesions. Even though the darker skin could becomedarker with treatment providing further contrast, we have found that thedifference in skin tone with the vitiliginous patches actuallysurprisingly decreased over time with treatment according to theinvention. Accordingly, the invention preferably relates to subjectswith Fitzpatrick skin type Ill, IV, V or VI, more preferably Fitzpatrickskin type IV, V or VI, most preferably Fitzpatrick skin type VI or VI.

Vitiligo is preferably scored using the VASI (Vitiligo Area ScoringIndex) and/or the Vitiligo European Task Force (VETF) scoring systems.These systems have been described in Hamzavi I, et al (2004),“Parametric modeling of narrowband UV-B phototherapy for vitiligo usinga novel quantitative tool: the Vitiligo Area Scoring Index.”ArchDermatol. 140(6):677-83; and in Taïeb A, Picardo M & VETF Members(2007). “The definition and assessment of vitiligo: a consensus reportof the Vitiligo European Task Force.”Pigment Cell Res. 20(1):27.35.

The pharmaceutical composition according to the invention may beadministered in a sustained-release delivery system as disclosed inInternational Patent Application No. PCT/AU2005/000181 (WO 2006/012667),or topically using a transdermal delivery system as disclosed inInternational Patent Application No. PCT/AU2005/001552 (WO 2006/037188).

It will be appreciated that the actual preferred amounts of thealpha-MSH analogue and corticosteroid, immunosuppressant,anti-inflammatory agent and/or photochemotherapeutic agent (hereinafterreferred to as the “active pharmaceutical ingredients”) will varyaccording to the specific compounds being utilized, the particularcompositions formulated, the mode of application, and the particularsitus and subject being treated. Dosages for a given host can bedetermined using conventional considerations, e.g. by customarycomparison of the differential activities of the subject compounds andof a known agent, e.g. by means of an appropriate conventionalpharmacological protocol. Physicians and formulators, skilled in the artof determining doses of pharmaceutical compounds, will have no problemsdetermining doses for prophylactically or therapeutically treatingvitiligo by administration of an amount of a pharmaceutical compositionof the invention by the methods described herein. In one aspect of thepresent invention, the pharmaceutical composition is administered in anamount which is effective to prophylactically or therapeutically treatvitiligo.

Any of the alpha-MSH analogues useful herein can be administered to asubject using a variety of administration or delivery techniques knownin the art. It is desirable to maintain low concentrations (e.g.concentrations of 0.001 ng to 10 ng/ml) of the alpha-MSH analogue in theplasma of the subject in the treatment of vitiligo. In one preferredembodiment the alpha-MSH analogue is administered in a prolonged releaseformulation such as described in WO 2006/012667, the disclosure of whichis included herein by cross reference. Therefore, the mode ofadministration will depend upon the subject to be treated and thealpha-MSH analogue selected. In various aspects, the alpha-MSH analoguescan be administered orally or parenterally. The term “oral” is usedherein to encompass administration of the compounds via the digestivetract. The term “parenteral” is used herein to encompass any route ofadministration, other than oral administration, by which the alpha-MSHanalogue is introduced into the systemic circulation which includes, butis not limited to, intravenous, intramuscular, subcutaneous,intraperitoneal, intradermal, ocular, inhalable, rectal, vaginal,transdermal, topical, buccal, sublingual, or mucosal administration. Theterm “mucosal” as used herein encompasses the administration of thecompounds by methods that employ the mucosa (mucous membranes) of thehuman body such as, but not limited to, buccal, intranasal, gingival,vaginal, sublingual, pulmonary, or rectal tissue. The term “transdermal”as used herein encompasses the administration of the compounds that gointo the skin or go through the skin using formulations such as, but notlimited to, transdermal formulations, buccal patches, skin patches, ortransdermal patches. The term “topical” as used herein encompassesadministration by applying conventional topical preparations such ascreams, gels, or solutions for localized percutaneous delivery and/or bysolution for systemic and/or localized delivery to areas such as, butnot limited to the eye, skin, rectum, and vagina.

In one aspect of the present invention, delivery systems composed ofdevices or compositions containing an alpha-MSH analogue together withone or more corticosteroid, immunosuppressant, anti-inflammatory agentor photochemotherapeutic agent can be manufactured that allow for thecontrolled-release, extended-release, modified-release,sustained-release, pulsatile-release, or programmed-release delivery ofthe active components in order to maintain concentration of the activecomponents in the plasma of the subject.

Depending on the delivery system or composition of a formulation orroute of administration chosen, drugs or active pharmaceuticalingredients can be delivered for hours, weeks, or months following asingle administration. Drug-delivery devices include, but are notlimited to pumps, needle-free injectors, metered-dose inhalers, and thelike. Transdermal compositions with or without penetration enhancersinclude but are not limited to transdermal patches, microneedles, andtransdermal formulations that achieve drug delivery using inotophoresis,sonophoresis, electroporation, thermoporation, perfusion, adsorption andabsorption. Other delivery systems include, but are not limited to,biodegradable of non-biodegradable rods or other shaped implants,fibers, microparticles, microspheres, microcapsules, nanospheres,nanocapsules, porous silicon nanoparticles, in situ gellingformulations, in situ bolus forming compositions, quick dissolvingtablets and the like, buccal patches, films, tablets, capsules, osmoticpressure driven formulations, liquid filled capsules, liposomes andother lipid based compositions and the like, pegalation and the like,hydrogel formulations, emulsions, microemulsions, and suspensions.

In one aspect of the present invention, polymeric delivery systems canbe microparticles including, but not limited to microspheres,microcapsules, nanospheres and nanoparticles comprising biodegradablepolymeric excipients, non-biodegradable polymeric excipients, ormixtures of polymeric excipients thereof, or the polymeric deliverysystems can be, but not limited to rods or other various shapedimplants, wafers, fibers, films, in situ forming boluses and the likecomprising biodegradable polymeric excipients, non-biodegradablepolymeric excipients, or mixtures thereof. These systems can be madefrom a single polymeric excipient or a mixture or blend of two or morepolymeric excipients.

A suitable polymeric excipient includes, but is not limited to, apoly(diene) such as poly(butadiene) and the like; a poly(alkene) such aspolyethylene, polypropylene, and the like; a poly(acrylic) such aspoly(acrylic acid) and the like; a poly(methacrylic) such as poly(methylmethacrylate), a poly(hydroxyethyl methacrylate), and the like; apoly(vinyl ether); a poly(vinyl alcohol); a poly(vinyl ketone); apoly(vinyl halide) such as poly(vinyl chloride) and the like; apoly(vinyl nitrile), a poly(vinyl ester) such as poly(vinyl acetate) andthe like; a poly(vinyl pyridine) such as poly(2-vinyl pyridine),poly(5-methyl-2-vinyl pyridine) and the like; a poly(styrene); apoly(carbonate); a poly(ester); a poly(orthoester) including acopolymer; a poly(esteramide); a poly(anhydride); a poly(urethane); apoly(amide); a cellulose ether such as methyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose, and the like; a celluloseester such as cellulose acetate, cellulose acetate phthalate, celluloseacetate butyrate, and the like; a poly(saccharide), a protein, gelatin,starch, gum, a resin, and the like. These materials may be used alone,as physical mixtures (blends), or as co-polymers. Derivatives of any ofthe polymers listed above are also contemplated.

In one aspect of the present invention, the polymeric excipient of thedelivery system includes a biocompatible, non-biodegradable polymer suchas, for example, a silicone, a polyacrylate; a polymer of ethylene-vinylacetate; an acyl substituted cellulose acetate; a non-degradablepolyurethane; a polystyrene; a polyvinyl chloride; a polyvinyl fluoride;a poly(vinyl imidazole); a chlorosulphonate polyolefin; a polyethyleneoxide; or a blend or copolymer thereof.

In another aspect, the polymeric excipient includes a biocompatible,biodegradable polymer such as, for example, a poly(lactide); apoly(glycolide); a poly(lactide-co-glycolide); a poly(lactic acid); apoly(glycolic acid); a poly(lactic acid-co-glycolic acid); apoly(caprolactone); a poly(orthoester); a poly(phosphazene); apoly(hydroxybutyrate) or a copolymer containing a poly(hydroxybutarate);a poly(lactide-co-caprolactone); a polycarbonate; a polyesteramide; apolyanhydride; a poly(dioxanone); a poly(alkylene alkylate); a copolymerof polyethylene glycol and a polyorthoester; a biodegradablepolyurethane; a poly(amino acid); a polyetherester; a polyacetal; apolycyanoacrylate; a poly(oxyethylene)/poly(oxypropylene) copolymer, ora blend or copolymer thereof.

In one aspect of the present invention, the delivery system comprises animplant or rod, wherein the implant or rod comprises a biodegradablepolymer, wherein the pharmaceutical composition of the invention isembedded within the implant or rod. In another aspect of the presentinvention, the pharmaceutical composition of the invention isencapsulated in an implant or rod composed ofpoly(lactide-co-glycolide), poly(lactide), poly(glycolide), or a mixturethereof. Lactide/glycolide polymers for drug-delivery formulations aretypically made by melt polymerization through the ring opening oflactide and glycolide monomers. Some polymers are available with orwithout carboxylic acid end groups. When the end group of thepoly(lactide-co-glycolide), poly(lactide), or poly(glycolide) is not acarboxylic acid, for example, an ester, then the resultant polymer isreferred to herein as blocked or capped. The unblocked polymer,conversely, has a terminal carboxylic group. In another aspect of thepresent invention, linear lactide/glycolide polymers are used; howeverstar polymers can be used as well. In certain aspects, high molecularweight polymers can be used for medical devices, for example, to meetstrength requirements. In other aspects, low molecular weight polymerscan be used for drug-delivery and vaccine delivery products whereresorption time and not material strength is as important. The lactideportion of the polymer has an asymmetric carbon. Commercially racemicDL-, L-, and D-polymers are available. The L-polymers are morecrystalline and resorb slower than DL-polymers. In addition tocopolymers comprising glycolide and DL-lactide or L-lactide, copolymersof L-lactide and DL-lactide are available. Additionally, homopolymers oflactide or glycolide are available.

In the case when the biodegradable polymer ispoly(lactide-co-glycolide), poly(lactide), or poly(glycolide), theamount of lactide and glycolide in the polymer can vary. In one aspectof the present invention, the biodegradable polymer contains 0 to 100mole %, 40 to 100 mole %, 50 to 100 mole %, 60 to 100 mole %, 70 to 100mole %, or 80 to 100 mole % lactide and from 0 to 100 mole %, 0 to 60mole %, 10 to 40 mole %, 20 to 40 mole %, or 30 to 40 mole % glycolide,wherein the amount of lactide and glycolide is 100 mole %. In anotheraspect of the present invention, the biodegradable polymer can bepoly(lactide), 85:15 poly(lactide-co-glycolide), 75:25poly(lactide-co-glycolide), or 65:35 poly(lactide-co-glycolide) wherethe ratios are mole ratios.

In one aspect of the present invention, when the biodegradable polymeris poly(lactide-co-glycolide), poly(lactide), or poly(glycolide), thepolymer has an intrinsic viscosity of from 0.15 to 1.5 dL/g, 0.25 to 1.5dL/g, 0.25 to 1.0 dL/g, 0.25 to 0.8 dL/g, 0.25 to 0.6 dL/g, or 0.25 to0.4 dL/g as measured in chloroform at a concentration of 0.5 g/dL at 30°C.

The amount of alpha-MSH analogue, corticosteroid, immunosuppressant,anti-inflammatory agent and/or photochemotherapeutic agent that isencapsulated or incorporated in the biodegradable polymer will varydepending upon the selection of the biodegradable polymer, theencapsulation or incorporation technique, and the amount of activepharmaceutical ingredients to be delivered to the subject. In one aspectof the present invention, the amount of active pharmaceuticalingredients encapsulated in the microcapsule, implant, or rod can be upto 50% by weight of the delivery system. In other aspects, the amount ofactive pharmaceutical ingredients encapsulated in the microcapsule,implant, or rod can be from 5 to 60, 10 to 50%, 15 to 40%, or 15 to 30%by weight of the delivery system.

In another aspect, where the alpha-MSH analogue in combination with oneor more corticosteroid, immunosuppressant, anti-inflammatory agent orphotochemotheapeutic agent is delivered by another delivery system suchas a transdermal formulation, the amount of active pharmaceuticalingredients in the formulation can be from 0.001 to 10%, or 0.05 to 5%by weight of the formulation.

Other pharmaceutically acceptable components can be encapsulated orincorporated in the delivery system in combination with the alpha-MSHanalogue, corticosteroid, immunosuppressant and/or anti-inflammatoryagent. For example, the pharmaceutically acceptable component caninclude, but is not limited to, a fatty acid, a sugar, a salt, awater-soluble polymer such as polyethylene glycol, a protein,polysaccharide, or carboxmethyl cellulose, a surfactant, a plasticizer,a high- or low-molecular-weight porosigen such as polymer or a salt orsugar, or a hydrophobic low-molecular-weight compound such ascholesterol or a wax. In another aspect, the delivery system comprisesan implant or rod, wherein the alpha-MSH analogue is [Nle⁴,D-Phe⁷]-alpha-MSH in the amount from 15% to 45% by weight of the implantor rod, wherein the rod or implant comprises poly(lactide) orpoly(lactide-co-glycolide) such as, for example, 85:15poly(lactide-co-glycolide).

Any of the delivery systems described herein can be administered usingtechniques known in the art. In one aspect of the present invention, thedelivery system can be administered subcutaneously to the subject. Inthis aspect, the duration of administration can vary depending upon theamount of active pharmaceutical ingredients that are encapsulated andthe biodegradable polymer selected. In another aspect of the presentinvention, the delivery system is administered subcutaneously to thesubject and releases the active pharmaceutical ingredients for a periodof at least 2, 4, 6, 8, 10 or 12 days. In another aspect of the presentinvention, the delivery system releases the active pharmaceuticalingredients in the subject for at least 1, 2 or 3 months. In variousother aspects, the delivery system releases the active pharmaceuticalingredients in the subject for 10 days, 15 days, 20 days, 25 days, or 30days.

In a preferred embodiment of the present invention the pharmaceuticalcomposition is administered to a subject when skin lesions are active.The term “active lesion” as used herein means incipient vitiligo lesionsof the skin, or incipient loss of pigmentation of the skin, migratingareas of depigmentation of the skin. Active lesions show clinicallydaily, weekly and monthly pigmentation (‘discolouring’) changes overtime.

The pharmaceutical compositions can be prepared using techniques knownin the art. In one aspect of the present invention, the composition isprepared by admixing the alpha-MSH analogue and corticosteroid,immunosuppressant and/or anti-inflammatory agent with apharmaceutically-acceptable carrier. The term “admixing” is defined asmixing the two components together so that there is no chemical reactionor physical interaction. The term “admixing” also includes the chemicalreaction or physical interaction between the alpha-MSH analogue,corticosteroid, immunosuppressant and/or anti-inflammatory agent and thepharmaceutically-acceptable carrier.

Pharmaceutically-acceptable carriers are known to those skilled in theart. These most typically would be standard earners for administrationto humans, including solutions such as sterile water, saline, andbuffered solutions at physiological pH.

Molecules intended for pharmaceutical delivery may be formulated in apharmaceutical composition. Pharmaceutical compositions may includecarriers, thickeners, diluents, buffers, preservatives, surface activeagents and the like in addition to the molecule of choice.Pharmaceutical compositions may also include one or more activeingredients such as antimicrobial agents, anti-inflammatory agents,anesthetics, and the like.

Preparations for administration include sterile aqueous or non-aqueoussolutions, suspensions, and emulsions. Examples of non-aqueous carriersinclude water, alcoholic/aqueous solutions, emulsions or suspensions,including saline and buffered media. Parenteral vehicles, if needed forcollateral use of the disclosed compositions and methods, include sodiumchloride solution, Ringer's dextrose, dextrose and sodium chloride,lactated Ringer's, or fixed oils. Intravenous vehicles, if needed forcollateral use of the disclosed compositions and methods, include fluidand nutrient replenishers, electrolyte replenishers (such as those basedon Ringer's dextrose), and the like. Preservatives and other additivesmay also be present such as, for example, antimicrobials, anti-oxidants,chelating agents, and inert gases and the like.

Formulations for topical administration may include, ointments, lotions,creams, gels, drops, ointments, suppositories, sprays, liquids andpowders. Conventional pharmaceutical carriers, aqueous, powder or oilybases, thickeners and the like may be necessary or desirable. The activepharmaceutical ingredients can be admixed under sterile conditions witha physiologically acceptable carrier and any preservatives, buffers,propellants, or absorption enhancers as may be required or desired.Reference is made to documents cited herein, e.g., U.S. Pat. No.5,990,091, WO 98/00166, and WO 99/60164, for the preparation ofcompositions for topical applications, e.g., viscous compositions thatcan be creams or ointments, as well as compositions for nasal andmucosal administration.

In the case when the composition is administered mucosally, ocularly,intranasally, or by inhalation, the formulation can be in the form of adrop, a spray, an aerosol, or a sustained release format. The spray andthe aerosol can be achieved through use of the appropriate dispenser.The sustained release format can be an ocular insert, erodiblemicroparticulates, swelling mucoadhesive particulates, pH sensitivemicroparticulates, nanoparticles/latex systems, ion-exchange resins andother polymeric gels and implants (Ocusert, Alza Corp., California;Joshi, A., S. Ping and K. J. Himmelstein, Patent Application WO91/19481). These systems maintain prolonged drug contact with theabsorptive surface preventing washout and nonproductive drug loss.

In a preferred embodiment of the present invention the pharmaceuticalcomposition according is administered to a human or domestic animalsubject. Most preferably the subject is a human subject.

Throughout this specification the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps.

All publications mentioned in this specification are herein incorporatedby reference. Any discussion of documents, acts, materials, devices,articles or the like which has been included in the presentspecification is solely for the purpose of providing a context for thepresent invention. It is not to be taken as an admission that any or allof these matters form part of the prior art base or were common generalknowledge in the field relevant to the present invention as it existedin Australia or elsewhere before the priority date of each claim of thisapplication.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notrestrictive.

EXAMPLE

Patients suffering from vitiligo were recruited in a trial investigatingthe efficacy of afamelanotide (Scenesse) in combination with NB-UVB incomparison with NB-UVB monotherapy. dult subjects with stable or slowlyprogressive vitiligo of 15-50% of total body depigmentation and withFitzpatrick skin types III-VI were included. Patients were diagnosedwith vitiligo within the past five years of study commencement and hadnot received NB-UVB treatment within six months of the screening visit.

Fifty-four patients were randomly assigned in equal numbers to one ofthe two treatment groups. Group A (active) received one month of thriceweekly NB-UVB monotherapy, followed by monthly doses of SCENESSE® (one16 mg afamelanotide implant administered underneath the skin as adissolvable implant on study days 28, 56, 84 and 112) in withcombination thrice weekly NB-UVB therapy for four months, and then afinal month of thrice weekly NB-UVB monotherapy. Group A patientsreceived a total of 72 NB-UVB treatments over the course of the 6 monthperiod. Group B (placebo) received thrice weekly NB-UVB monotherapy forsix months, for a total of 72 NB-UVB treatments over the course of the 6month period.

NB-UVB light of 311 nm was used on the entire body for a maximum of 6minutes, three times a week on non-consecutive days for the 6 monthstudy period with a required minimum number of 10 NB-UVB treatments permonth. NB-UVB treatment was started at the same fixed dose of 150mJ/cm². A maximum of 3 J/cm² was used. For the following treatment, thedose could be adjusted as follows: the dose could be increased with10-15% compared to the previous dose (if no erythema occurred), kept thesame (if minimal erythema occurred following the previous treatment), orreduced with 5-10% (if the mild to moderate erythema occurred).

Efficacy was measured using the Vitiligo Area Scoring Index (VASI) andstandardized Vitiligo European Task Force (VETF) scores between day 0and day 168. The VASI is a validated measure to assess the extent ofvitiligo involvement in patients; the VETF score equally measures skinsurface to assess the areas affected by vitiligo. Speed ofrepigmentation, depth of repigmentation, stability of pigmentation, andsafety of combination therapy were recorded.

Forty-one (75.9%, n=41) patients completed the treatment. Thirteenpatients withdrew due to their inability to comply with the demandingtreatment protocol, or, in the case of five patients, due to theintensity of pigmentation experienced.

The extent of repigmentation in the SCENESSE®/NB-UVB group wassignificantly greater than observed in the NB-UVB-alone group (VASI,p=0.025; VETF p=0.023; 95% CI).

Significantly better, more complete and deeper repigmentation wasobserved for those patients with the darkest skin complexion havingFitzpatrick skin type IV to VI (n=24) who had received the combinationtherapy in comparison with those patients on monotherapy (p=0.046; 95%CI).

The VASI scores showed that those patients who had received thecombination therapy achieved earlier repigmentation than those onmonotherapy (median time 43 days versus 68 days, p=0.086; 95% CI).

Overall the combined treatment was well tolerated and no seriousdrug-related adverse events were reported.

It can be concluded that the proposed combination therapy of NB-UVB withSCENESSE® enables a faster and more complete repigmentation for peoplewith vitiligo. After combination treatment with NB-UVB light treatmentled to excellent maintenance of repigmentation. Patients withFitzpatrick skin types IV, V and VI responded especially well totreatment. This is particularly interesting as vitiligo tends to be mostvisible for these patients. Overall, the feedback from patients andphysicians has been very positive.

EMBODIMENTS

Embodiment 1. A pharmaceutical composition for treating or preventingvitiligo comprising an alpha-MSH analogue selected from compounds of theformula:R₁—W—X—Y—Z—R₂

-   -   Wherein    -   R₁ is absent, n-Pentadecanoyl, Ac, 4-phenylbutyrul, Ac-Gly-,        Ac-Met-Glu, Ac-Nle-    -   Glu-, or Ac-Tyr-Glu-;    -   W is -His- or -D-His-;    -   X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pNO₂)D-Phe⁷-;    -   Y is -Arg- or -D-Arg-;    -   Z is -Trp- or -D-Trp-; and    -   R₂ is —NH₂; -Gly-NH₂; or -Gly-Lys-NH₂.

Embodiment 2. A pharmaceutical composition for treating or preventingvitiligo comprising a linear alpha-MSH analogue selected from the groupconsisting of:

Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly- Pro-Val-NH₂,Ac-Ser-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly- Pro-Val-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Orn-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Orn-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dab-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dab-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dpr-NH₂,Ac-Nle-Glu-His-Phe-Arg-Trp-Lys-NH₂, Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-NH₂,or a cyclic alpha-MSH analogue selected from the group consisting of:

wherein Ala=alanine, Arg=arginine, Dab=2,4-diaminobutyric acid,Dpr=2,3-diaminopropionic acid, Glu=glutamic acid, Gly=glycine,His=histidine, Lys=lysine, Met=methionine, Nie=norleucine,Orn=ornithine, Phe=phenylalanine, (pNO2)Phe=paranitrophenylalanine,Pig=phenylglycine, Pro=proline, Ser=serine, Trp=tryptophan,TrpFor=N¹⁻-formyl-tryptophan, Tyr=tyrosine, Val=valine.

Embodiment 3. A pharmaceutical composition for treating or preventingvitiligo comprising an alpha-MSH analogue selected from the groupconsisting of:

Embodiment 4. A pharmaceutical composition for treating or preventingvitiligo comprising an alpha-MSH analogue selected from the groupconsisting of:

[Nle⁴, D-Phe⁷]-alpha-MSH₄₋₁₀, [Nle⁴, D-Phe⁷]-alpha-MSH₄₋₁₁,[Nle⁴, D-Phe⁷, D-Trp⁹]-alpha-MSH₄₋₁₁, [Nle⁴, D-Phe⁷]-alpha-MSH₄₋₉.

Embodiment 5. A pharmaceutical composition for treating or preventingvitiligo comprising an alpha-MSH analogue selected from the groupconsisting of: [Nle⁴, D-Phe⁷]-alpha-MSH.

Embodiment 6. The pharmaceutical composition according to embodiments 1to 5, further comprising one or more agents selected from the groupconsisting of corticosteroids, immunosuppressants, anti-inflammatoryagents and photochemotherapeutic agents together with a pharmaceuticallyacceptable carrier or diluent.

Embodiment 7. The pharmaceutical composition according to embodiment 6,wherein the corticosteroid is selected from mometasone furoate,betamethasone, dexamethasone, hydrocortisone, methylprednisolone,prednisolone and cortisone.

Embodiment 8. The pharmaceutical composition according to embodiment 6,wherein the corticosteroid is selected from mometasone furoate andbetamethasone.

Embodiment 9. The pharmaceutical composition according to embodiment 6,wherein the immunosuppressant is selected from cytostatics includingcytotoxic antibiotics, alkylating agents and antimetabolites,antibodies, glucocorticoids, drugs acting on immunophilins includingcyclosporine, tacrolimus and sirolimus, interferons, azathioprine,5-fluorouracil and opioids.

Embodiment 10. The pharmaceutical composition according to embodiment 6,wherein the immunosuppressant is selected from tacrolimus,betamethasone, azathioprine and levamisole.

Embodiment 11. The pharmaceutical composition according to embodiment 6,wherein the anti-inflammatory agent is selected from betamethasone andcortisone.

Embodiment 12. The pharmaceutical composition according to embodiment 6,wherein the photochemotherapeutic agent is psoralen.

Embodiment 13. A method for treating or preventing vitiligo in a subjectcomprising administering to the subject a therapeutically orprophylactically effective amount of a pharmaceutical compositioncomprising an alpha-MSH analogue according to embodiments 1 to 12.

Embodiment 14. The method according to embodiment 13, further comprisingthe step of exposing the subject to an effective amount of ultra-violetlight (UV), in particular ultra-violet A light (UVA), when thepharmaceutical composition administered to the subject comprises one ormore photochemotherapeutic agents.

Embodiment 15. The method according to embodiments 13 or 14, wherein thepharmaceutical composition is administered in a sustained-releasedelivery system, topically using a transdermal delivery system or in aprolonged release formulation.

Embodiment 16. The method according to embodiments 13 to 15, wherein theconcentration of the alpha-MSH analogue in the plasma of the subject inthe treatment of vitiligo is maintained in a low concentration range of0.001 ng/ml to 10 ng/ml.

Embodiment 17. The method according to embodiments 13 to 16, wherein thepharmaceutical composition is administered orally or parenterally.

Embodiment 18. A delivery system composed of devices or compositionscontaining an alpha-MSH analogue together with one or morecorticosteroids, immunosuppressants, anti-inflammatory agents orphotochemotherapeutic agents according to embodiments 1 to 12, whereinthe delivery system allows for the controlled-release, extended-release,modified-release, sustained-release, pulsatile-release, orprogrammed-release delivery of the active components in order tomaintain concentration of the active components in the plasma of thesubject.

The invention claimed is:
 1. A method for treating vitiligo in a subjectcomprising administering to the subject a therapeutically effectiveamount of an alpha-MSH analogue, wherein the alpha-MSH analogue is aderivative of alpha-MSH wherein (i) one or more amino acid residues aredeleted from the N-terminal end, the C-terminal end, or both compared toa native alpha-MSH molecule; and/or (ii) one or more amino acid residuesare substituted with a natural, non-natural or synthetic amino acidresidue compared to a native alpha-MSH molecule; and/or (iii) anintramolecular interaction occurs, thereby forming a cyclic derivative.2. The method according to claim 1, further comprising the step ofexposing the subject to an effective amount of narrow band ultraviolet B(NB-UVB) light.
 3. The method according to claim 2, wherein the subjectis exposed to NB-UVB light treatment and to alpha-MSH analogue at thesame time.
 4. The method according to claim 2, wherein the subject isexposed to NB-UVB light treatment during a period of at least 1 weekbefore administration of the alpha-MSH analogue.
 5. The method accordingto claim 2, wherein the subject is exposed to NB-UVB light treatmentduring a period of at least 1 week after administration of the alpha-MSHanalogue.
 6. The method according to claim 1, wherein the subject hasFitzpatrick skin type IV, V or VI.
 7. The method according to claim 1,wherein the alpha-MSH analogue is present in the blood plasma of thesubject at a concentration of from 0.001 ng/ml to 10 ng/ml for a periodof at least 2 days.
 8. The method according to claim 1, wherein thealpha-MSH analogue is systemically administered by subcutaneous,intramuscular, intraperitoneal or intravenous injection.
 9. The methodaccording to claim 1, wherein the alpha-MSH analogue is selected fromcompounds of the formula:R₁—W—X—Y—Z—R₂ wherein R₁ is absent, n-Pentadecanoyl, Ac,4-phenylbutyrul, Ac-Gly-, Ac-Met-Glu, Ac-Nle-Glu-, or Ac-Tyr-Glu-; W is-His- or -D-His-; X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pN02)D-Phe-;Y is -Arg- or -D-Arg-; Z is -Trp- or -D-Trp-; and R₂ is —NH₂; -Gly-NH₂;or -Gly-Lys-NH₂, or a linear alpha-MSH analogue selected from the groupconsisting of: Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂, Ac-Ser-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂, Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Orn-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Orn-NH₂,Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dab-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dab-NH₂,Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dpr-NH₂,Ac-Nle-Glu-His-Phe-Arg-Trp-Lys-NH₂, andAc-Nle-Asp-His-Phe-Arg-Trp-Lys-NH₂,

or a cyclic alpha-MSH analogue selected from the group consisting of:

or an alpha-MSH analogue selected from the group consisting of:


10. The method according to claim 1, wherein the alpha-MSH analogue is[Nle⁴, D-Phe⁷]-alpha-MSH.
 11. The method according to claim 1, whereinthe alpha-MSH analogue is administered in a composition furthercomprising one or more agents selected from the group consisting ofcorticosteroids, immunosuppressants, anti-inflammatory agents andphotochemotherapeutic agents together with a pharmaceutically acceptablecarrier or diluent.